Multi-Omics Analysis Of Nf1 Deficiency In Various Cell Types Implicates Roles Outside Of Ras For Cells And Their Microenvironment

Authors

• Christian Xavier Fay, University of Alabama at Birmingham

Advisor(s)

Deeann Wallis

Committee Member(s)

David Crossman
Elizabeth Worthey
James Mobley
Yabing Chen

School

Joint Health Sciences (Interdisciplinary)

Document Type

Dissertation

Department (new version)

Genetics

Date of Award

9-9-2024

Abstract

Neurofibromatosis type 1 is an autosomal dominant disease in which many patients develop the hallmark feature, neurofibromas, benign tumors that develop along the peripheral nerves. Currently there is no known cure for NF1, and more than 3000 germline pathogenic variants (PVs) in NF1 have been observed. The neurofibromin gene encodes the 320kDa NF1 protein which has multiple predicted functions. Its most under-stood molecular role is in binding GTP-Ras and stimulating Ras-GTPase to cleave GTP to GDP and inactivate Ras signaling. In fact, the only FDA-approved therapeutic is the MEK inhibitor selumetinib which acts downstream of Ras. NF1 also has Ras independent functions and multiple putative protein-protein interaction domains. While NF1 is ex-pressed ubiquitously, expression levels are highest in adult neuronal cells. Loss of hetero-zygosity of the NF1 gene can lead to the development of tumors. In addition to tumors, there is a wide range of phenotypic presentations that arise including: skeletal abnormalities, café-au-lait spots (CALMs), social and behavioral problems, attention deficit, and learning disabilities. Additionally, females under the age of 50 have up to a 4.9-fold high-er likelihood of developing breast cancer compared to the general population. Herein, we first examen how variants of NF1 contribute to mammary tumorigenesis in novel NF1 rat models. We show how NF1 variants affect estrogen signaling and impact immune cells which presumably alters both the microenvironment and tumor landscape. Further we de-scribe how complete loss of NF1, or clinically relevant PVs of NF1, affect the proteome and protein interactors in Schwann cells. We observed altered mitochondrial metabolism, (also seen in rat mammary tumors). Lastly, we assess how selumetinib affects both the tumor and microenvironment of cutaneous neurofibromas. We demonstrate how selumetinib affects specific cell types causing changes in both ligand-receptor interactions and cellular states post selumetinib treatment. Our data contributes to the field’s understanding of cell-type specific effects of both NF1 variants and therapeutics (selumetinib) on disease progression and the tumor microenvironment. Altogether, this work defines multiple NF1 functions and provides new pathways outside of Ras for therapeutics targeting including targeting estrogen signaling, mitochondrial metabolism and immune suppression.

ProQuest ID

https://proquest.com/docview/3101942750